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  • Book
    Abdulrasheed A. Alabi.
    Digital2016
    Regulated exo-endocytosis is essential for the function of many intercellular signaling networks. Using a new optical nanosensor termed pHdot, I explore the molecular and cellular signals that tune the balance between two modes of vesicle fusion and recycling: kiss-and-run (KR) and full collapse fusion (FF) in hippocampal synapses in primary culture. Stimulation after a period of rest generates a frank initial rise in pHdot fluorescence, an unmistakeable signature of early phase KR. The prevalence of KR was dependent on the available pool of readily releasable vesicles and modulated by internal Ca2+ dynamics. Intriguingly, pharmacological inhibition of the Ca2+-dependent phosphatase calcineurin and stimulation of synapses with phorbol esters had dramatic yet opposing effects on fusion mode balance; providing a means of turning KR "on" or "off" respectively. Emerging data further suggests calcineurin facilitates a molecular switch from KR to FF that is dependent on actin dynamics and the F-BAR domain-containing protein syndapin I. Altogether, this body of work provides mechanistic insight into what appears to be a rather complex molecular choreography underlying kiss-and-run fusion at small, central synapses. The rich set of modulatory effects described could conceivably account for disparate reports on the prevalence of kiss-and-run at nerve terminals, a source of longstanding controversy. More exciting however is the likelihood that these findings reflect the diversity of signals and proteins that participate in shaping the energetics of fusion pore formation thus providing a glimpse into the intricate biochemical milieu that a vesicle navigates to direct its dynamic release properties.